The IL17F and IL17RA Genetic Variants Increase Risk of Cerebral Malaria in Two African Populations

Cerebral malaria (CM) is a neurological complication of infection with Plasmodium falciparum that is partly caused by cytokine-mediated inflammation. It is not known whether interleukin-17 (IL-17) cytokines, which regulate inflammation, control the development of CM. To evaluate the involvement of IL-17 cytokines in CM, we analyzed 46 common polymorphisms in IL17A, IL17F, and IL17RA (which encodes the common receptor chain of the members of the IL-17 family) in two independent African populations. A case-control study involving 115 Nigerian children with CM and 160 controls from the community (CC) showed that IL17F reference single nucleotide polymorphism (SNP) 6913472 (rs6913472) (P = 0.004; odds ratio [OR] = 3.12), IL17F rs4715291 (P = 0.004; OR = 2.82), IL17RA rs12159217 (P = 0.01; OR = 2.27), and IL17RA rs41396547 (P = 0.026; OR = 3.15) were independently associated with CM. A replication study was performed in 240 nuclear Malian family trios (two parents with one CM child). We replicated the association for 3 SNPs, IL17F rs6913472 (P = 0.03; OR = 1.39), IL17RA rs12159217 (P = 0.01; OR = 1.52), and IL17RA rs41396547 (P = 0.04; OR = 3.50). We also found that one additional SNP, IL17RA rs41433045, in linkage disequilibrium (LD) with rs41396547, was associated with CM in both Nigeria and Mali (P = 0.002; OR = 4.12 in the combined sample). We excluded the possibility that SNPs outside IL17F and IL17RA, in strong LD with the associated SNPs, could account for the observed associations. Furthermore, the results of a functional study indicated that the aggravating GA genotype of IL17F rs6913472 was associated with lower IL-17F concentrations. Our findings show for the first time that IL17F and IL17RA polymorphisms modulate susceptibility to CM and provide evidence that IL-17F protects against CM.     

The potential for using protein vaccines to protect against otitis media caused by Streptococcus pneumoniae

Potential vaccine strategies against otitis media are to prevent (1) symptomatic infections in the middle ear and/or (2) carriage of pneumococci and thereby subsequent middle ear infections. The possibility of using immunity to virulence proteins of pneumococci to elicit immunity against pneumococci has been examined. PspA has been found to have efficacy against otitis media in animals. Vaccination with a mixture of PsaA and PspA has been observed to offer better protection against nasal carriage in mice, than vaccination with either protein alone. PspA and pneumolysin have been shown to elicit protection against invasive infections. The inclusion of a few of these proteins into the polysaccharide-protein conjugate vaccines may be able to enhance their efficacy against otitis media and might be able to constitute a successful all-protein pneumococcal vaccine.     

Therapy for small cell lung cancer using carboplatin, ifosfamide, etoposide (without dose reduction), mid-cycle vincristine with thoracic and cranial irradiation

The aim of this study was to assess the efficacy and toxicity of intensive chemotherapy, administered without dose reduction, with cranial and thoracic radiotherapy given when possible as a single fraction in small cell lung cancer. 87 patients were eligible on the basis of good performance status, normal or near normal biochemistry and clinical staging, 73 limited and 14 extensive stage, computed tomography scanning was not mandatory. Six cycles of carboplatin, ifosfamide and etoposide with vincristine on day 15 at 4 weekly intervals were planned. Dosages were not reduced in response to myelosuppression. Prophylactic cranial irradiation (PCI) as a single fraction after the first cycle and thoracic irradiation (when possible as a single fraction) following the third cycle were delivered. Seventy-two per cent of patients completed the protocol. Complete response rate was 55% and 26% of patients had a partial response. The median nadirs of neutropenia were 0.5 × 10⁹/l and thrombocytopenia 14 × 10⁹/l, with 6% probable treatment-related deaths. Performance status and dyspnoea improved markedly to normal or near normal levels following the second course. Brain metastases occurred in 13% of patients. The median survival was 16.2 months with a 2-year survival of 31% (95% confidence interval, 24–41%) for a minimum follow-up of 26 months. These results compare favourably with other combined modality studies, using multiple radiotherapy fractions with cisplatin-based combinations and dosage reduction for patients staged in more anatomical detail. The toxicity spectrum and efficacy data could lead to the use of this chemotherapy regimen with haematopoietic growth factors and, in the future, peripheral blood progenitor cell rescue.     

Unilateral pulmonary artery occlusion inhibits growth of metastatic sarcoma in the rat lung

Tumors depend on their blood supply for growth. The blood supply to metastatic neoplasia of lung is usually from the pulmonary circulation or both the pulmonary and systemic circulation. The antineoplastic effect of pulmonary artery occlusion was investigated in a rat model of methylcholanthrene-induced metastatic pulmonary sarcoma. Left pulmonary artery ligation was performed on day 7 after tumor inoculation, and animals were sacrificed on day 14. The tumor burden of the left lung decreased 44% when compared with the control group. The survival of non-tumor-bearing rats undergoing left pulmonary artery ligation for 24 hours followed by right pneumonectomy after 2 weeks was also studied. No significant lung damage after a period of left pulmonary artery ligation was seen, as evidenced by both survival after contralateral right pneumonectomy and histology. Balloon occlusion of pulmonary artery, together with regional chemotherapy for patients with lung metastases, may warrant investigation. © 1994 Wiley-Liss, Inc.     

Immunization of healthy adults with a single recombinant pneumococcal surface protein A (PspA) variant stimulates broadly cross-reactive antibodies to heterologous PspA molecules

Pneumococcal surface protein A (PspA) is a highly variable protein found on all strains of pneumococci. To be successful, a PspA-based vaccine for S. pneumoniae must induce antibodies that are broadly cross-reactive. To address whether cross-reactive antibodies could be induced in man, we evaluated serum from adults immunized with recombinant clade 2 PspA from strain Rx1. Immunization with 5-125 microg rPspA lead to a significant increase in circulating anti-PspA antibodies, as well as antibodies reactive to heterologous rPspA molecules. Increased binding of post-immune sera to 37 pneumococcal strains expressing a variety of PspA and capsule types was observed, versus pre-immune sera. The extent of cross-clade reactivity of human anti-rPspA followed roughly the amount of sequence homology to the non-clade 2 antigens. It is hypothesized that priming of humans by natural exposure to S. pneumoniae contributes to the breadth of the cross-reactivity of antibody to PspA.     

Successful human pregnancy following in vitro fertilization using frozen semen

Frozen-thawed husband's semen was utilized for insemination of spouse's oocytes in vitro. Postthhaw semen had a low motility (40%) with a poor forward progression (+2), which subsequently decreased rapidly in the regalarly used Ham's F-10 medium (pH 7.42, 280 mosmoll kg) supplemented with 7.5% fetal cord serum. When Fam's F-10 was supplemented with an additional 0.5 mmol each of magnesium sulfate (MgSO₄) and potassium bicarbonate (KHCO₃) at a higher pH (pH 7.69, 280 mosmol/kg), the sperm maintained their motility and forword progression and fertilized all the oocytes, which subsequently cleaved and developed into normal embryos. Transfer of therse embryos resulted in a normal pregnancy. Our results indicate that cryopreserved semen of poor quality can be successfully employed for an in vitro fertilization-embryo transfer (IVF-ET) program, especially when MgSO₄ and KHCO₃ are used in Ham's F-10 at a higher pH.     

High-dose immune suppression and autologous hematopoietic stem cell transplantation in refractory Crohn disease

Two patients with severe Crohn disease, defined by a Crohn Disease Activity Index (CDAI) higher than 250 despite anti-tumor necrosis factor alpha (TNF-alpha), were treated by intense immune suppression and autologous hematopoietic stem cell transplantation (HSCT). Stem cells were mobilized from the peripheral blood using cyclophosphamide (2.0 g/m2) and granulocyte colony-stimulating factor (G-CSF; 5 micro g/kg/d), enriched ex vivo by CD34+ selection, and reinfused after immune conditioning with cyclophosphamide (200 mg/kg) and equine anti-thymocyte globulin (ATG; 90 mg/kg). Patients have remained in remission (CDAI < 100) for 1 year since HSCT. We conclude that further HSCT studies for severe Crohn disease appear warranted.     

Parent-child conflict and the comorbidity among childhood externalizing disorders

BACKGROUND: Previous research has suggested that substantial comorbidity exists among childhood externalizing disorders, specifically attention-deficit/hyperactivity disorder (ADHD), oppositional defiant disorder (ODD), and conduct disorder (CD). Moreover, parent-child conflict predicts each of these disorders. Our goals were to determine whether parent-child conflict was associated with the comorbidity among ADHD, CD, and ODD, and to explicitly examine the etiology of this association via a genetically informative design. METHODS: We compared the fit of the following 2 biometric models: the 2-factor common-pathway model, which examined genetic and environmental contributions to the relationship between conflict and the covariation among the 3 disorders, and the Cholesky model, which examined the relationship between conflict and each disorder individually. The sample consisted of 808 same-sex 11-year-old twin pairs from the Minnesota Twin Family Study, a population-based sample of Minnesota twins and their families. Main outcome measures included symptom counts for ADHD, CD, and ODD, obtained from structured interviews administered to twins and their mothers. Parent-child conflict was assessed via mother and twin reports of the Parental Environment Questionnaire. RESULTS: The 2-factor model provided a better fit to the data. These results indicated that conflict accounted for 33% of the covariation among the disorders, via genetic and environmental factors. CONCLUSIONS: Parent-child conflict appears to act as a common vulnerability that increases risk for multiple childhood disorders. Furthermore, this association is mediated via common genetic and environmental factors. These findings support the idea that the comorbidity among these disorders partially reflects core psychopathological processes in the family environment that link putatively separate psychiatric disorders.